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Targeting mutant p53 for efficient cancer therapy
Abstract
The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. Wild-type p53 can suppress tumour development by multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour cell death and rapid tumour progression. The high frequency of TP53 mutation in tumours has prompted efforts to restore normal function of mutant p53 and thereby trigger tumour cell death and tumour elimination. Small molecules that can reactivate missense-mutant p53 protein have been identified by different strategies, and two compounds are being tested in clinical trials. Novel approaches for targeting TP53 nonsense mutations are also underway. This Review discusses recent progress in pharmacological reactivation of mutant p53 and highlights problems and promises with these strategies.
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Suppression of Nonsense Mutations by New Emerging Technologies
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“P53-targeting strategies are an interesting lead for investigation (72,73), although no HNSCC-specific trials with small molecules targeting p53 have been found in our research.”
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Triangular Relationship between p53, Autophagy, and Chemotherapy Resistance
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“Unfortunately, the p53 pathway is often inactivated or functions in an antagonistic manner towards drug effectiveness [9,10].”
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Gomes, A. S., Ramos, H., Inga, A., Sousa, E., & Saraiva, L. (2021) · Cancers · doi:10.3390/cancers13133344 · Cited by 63
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BackgroundInfluentialDiscovery of a Potent and Selective Degrader for USP7
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“Since mutations in TP53 gene are present in the majority of DIPG cases, and given the increased tumor aggressiveness and worse overall prognosis associated with TP53 mutations DIPG, we investigated the efficacy of mutant p53 targeting with APR-246, a molecular agent shown to form covalent bonds with mutant p53 protein…”
BackgroundTP53 in Biology and Treatment of Osteosarcoma
Synoradzki, K. J., Bartnik, E., Czarnecka, A. M., Fiedorowicz, M., Firlej, W., Brodziak, A., Stasinska, A., Rutkowski, P. L., & Grieb, P. (2021) · Cancers · doi:10.3390/cancers13174284 · Cited by 66
“Most of the mutations are missense, but about 10% are nonsense mutations, which lead to the production of truncated p53 proteins [70].”
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“Cellular stress disrupts MDM2 binding to p53 by phosphorylation of both proteins and stimulates p53 acetylation, leading to p53 accumulation and activation [79].”
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“As the most widely investigated and clinically advanced p53 mutant-restoring compound, APR-246 exhibits anticancer activity in a variety of in vivo and in vitro preclinical cancer systems including models expressing mutant p53 [9].”
BackgroundMETTL7B Is Required for Cancer Cell Proliferation and Tumorigenesis in Non-Small Cell Lung Cancer
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“P53 is the most frequently mutated gene in cancer and many mutant p53 proteins exert oncogenic gain-of-function (GOF) properties that promote cancer cell growth and metastasis (Senturk et al., 2014; Bykov et al., 2018), however, the underlying mechanism remains unclear.”
BackgroundAnticancer Effect of Deuterium Depleted Water - Redox Disbalance Leads to Oxidative Stress
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“transcription factor (32), which regulates more than 2500”
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Nanoreceptors promote mutant p53 protein degradation by mimicking selective autophagy receptors
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“Given its widespread presence in human cancers and key role in tumour progression, targeting GOF of mutp53 is an attractive therapeutic strategy 14–17 .”
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Identification of Small Molecules that Modulate Mutant p53 Condensation
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“Compounds that directly bind to and stabilize mutant p53 have the potential to modulate p53 misfolding, condensation, and aggregation (Bykov et al., 2018; Li et al., 2019; Safari et al., 2019; Silva et al., 2018).”
BackgroundResultA comprehensive study of p53 protein
Patil, M. R., & Bihari, A. (2022) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30331 · Cited by 57
“In 2017, Bykov et al.(257) highlight new developments and several approaches in the pharmacological reactivation of mutant p53.”
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CENP-A overexpression promotes distinct fates in human cells, depending on p53 status
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Mutant p53 in cell-cell interactionsPreprint
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“However, APR-246 and its related compounds also show a variety of p53-independent activities that could underlie therapeutic efficacy (Bykov et al. 2018; Eriksson et al. 2019).”
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“Nowadays, three main strategies are available, including (i) the restoration of wild-type P53 activity by inhibiting its binding with MDM2/4 proteins [9,10]; (ii) the reactivation of the wild-type function in the mutant P53 protein [11] and (iii) the elimination of the undesired GOF activities through degradation of t…”
MethodCathepsin L activated by mutant p53 and Egr-1 promotes ionizing radiation-induced EMT in human NSCLC
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“However, more than 50% of human tumors harbor mutations in the p53 gene, and most tumors had dysfunctional p53 signaling.(23) The dysfunction and inactivation of p53 was also closely correlated with NPC initiation, development, and radioresistance.”
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“On basis of mutations subtypes, TP53 mutations showed a remarkable preference for missense mutations over nonsense and frameshift mutations that are commonly dominant in other tumor suppressor genes such as RB1, adenomatous polyposis coli (APC), and PTEN (44).”
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“Somatic TP53 mutations are the most frequent in most human cancers and eliminate its tumor suppressor functions as well as promote oncogenic properties (5).”
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Curaxin CBL0137 Exerts Anticancer Activity via Diverse Mechanisms
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“FACT binds to CK2 to form a complex, which further induces Ser392 phosphorylation of p53; otherwise, p53 is degraded by MDM2 (2, 7, 33) (Figure 1).”
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“For Chromatin Immunoprecipitation (ChIP) analysis, protein/DNA complexes were cross-linked by adding formaldehyde (1% final concentration) in living cells, as previously reported [16], and chromatin extracts were incubated overnight at 4 ◦C with anti-NRF2 antibody (ab62352) (Abcam, Cambridge, UK).”
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Leveraging aptamers for targeted protein degradation
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“p53 proteoforms, were reported to have oncogenic functions [37].”
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“Wild-type p53 can suppress tumor development by multiple pathways [68].”
BackgroundDrug-Resistance Mechanism and New Targeted Drugs and Treatments of Relapse and Refractory DLBCL
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“TP53 gene is an important tumor suppressor gene, which is related to apoptosis or cell cycle regulation.(4,41) About 22% of DLBCL patients may have TP53 mutations, and the prognosis of these patients is generally poor.”
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SLC7A11 Is a Superior Determinant of APR-246 (Eprenetapopt) Response than TP53 Mutation Status
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The deaminase APOBEC3B triggers the death of cells lacking uracil DNA glycosylase
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Genomic profiling of platinum-resistant ovarian cancer: The road into druggable targets
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Targeting Mutant p53 for Cancer Treatment: Moving Closer to Clinical Use?
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“Based on several preclinical studies showing anti-cancer activity [8,44], eprenetapopt was investigated for potential toxicity in a phase I clinical trial [53].”
BackgroundInfluentialOpposing Roles of Wild-type and Mutant p53 in the Process of Epithelial to Mesenchymal Transition
Semenov, O., Daks, A. A., Fedorova, O., Shuvalov, O. Y., & Barlev, N. A. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.928399 · Cited by 47
“Therefore, perhaps not surprisingly, TP53 mutations are observed in more than 50% of human cancers (Bykov et al., 2018).”
Backgroundp53 immunostaining pattern is a useful surrogate marker for TP53 gene mutations
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Natural modulators of the hallmarks of immunogenic cell death
Radogna, F., Dicato, M. A., & Diederich, M. F. (2019) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.12.016 · Cited by 47
Mechanisms of long non‐coding RNA function in colorectal cancer tumorigenesis
Poursheikhani, A., Abbaszadegan, M. R., & Kerachian, M. A. (2020) · Asia-Pacific Journal of Clinical Oncology · doi:10.1111/ajco.13452 · Cited by 46
p53 and Zinc: A Malleable Relationship
Ha, J., Prela, O., Carpizo, D. R., & Loh, S. N. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.895887 · Cited by 48
“For some 25 years, numerous research groups have dissected how common tumorigenic mutations affect the structure, function, and folding of p53 [reviewed in (Joerger and Fersht, 2016; Loh, 2020; Bykov et al., 2018)].”
BackgroundTumor cell-derived extracellular vesicles for breast cancer specific delivery of therapeutic P53
Jiao, Y., Tang, Y., Li, Y., Liu, C., He, J., Zhang, L., & Guan, Y. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.07.020 · Cited by 46
Rocca, V., Blandino, G., D’Antona, L., Iuliano, R., & Agostino, S. D. (2022) · Cancers · doi:10.3390/cancers14153664 · Cited by 50
Prolyl Isomerase Pin1 in Human Cancer: Function, Mechanism, and Significance
Pu, W., Zheng, Y., & Peng, Y. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00168 · Cited by 49
“Cancer cells possess an excessive cell proliferation ability that sustains proliferative signaling (Samatar and Poulikakos, 2014; Bykov et al., 2018).”
BackgroundZhao, L., Qu, X., Wu, Z., Li, Y., Zhang, X., & Guo, W. (2020) · Aging · doi:10.18632/aging.103502 · Cited by 48
“resulting in significantly lower levels of the TP53 protein as well as loss of function [12, 20, 21].”
BackgroundA balancing act: using small molecules for therapeutic intervention of the p53 pathway in cancer
Miller, J. J., Gaiddon, C., & Storr, T. (2020) · Chemical Society Reviews · doi:10.1039/d0cs00163e · Cited by 47
Neoantigens in Hematologic Malignancies
Biernacki, M. A., & Bleakley, M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00121 · Cited by 47
“TP53 mutations occur in malignancies of all origins (99), including all types of hematologic malignancies (100, 101, 158) (Table 2).”
BackgroundExtracellular Vesicles: Messengers of p53 in Tumor–Stroma Communication and Cancer Metastasis
Pavlakis, E., Neumann, M. M., & Stiewe, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249648 · Cited by 45
Small-molecule correctors and stabilizers to target p53
Fallatah, M. M. J., Law, F. V., Chow, W. A., & Kaiser, P. (2023) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2023.02.007 · Cited by 44
Therapeutic potential of p53 reactivation in prostate cancer: Strategies and opportunities
Kumari, S., Sharma, V., Tiwari, R., Maurya, J. P., Subudhi, B. B., & Senapati, D. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.174807 · Cited by 47
Chen, C., Fu, G., Guo, Q., Xue, S., & Luo, S. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.09.087 · Cited by 45
Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics
Kogan, S., & Carpizo, D. R. (2018) · Cancers · doi:10.3390/cancers10060166 · Cited by 45
“Numerous approaches have been described, many of which have been discovered in the last ten years and are summarized in several reviews [2,21,22].”
BackgroundTargeting mitochondria with Au–Ag@Polydopamine nanoparticles for papillary thyroid cancer therapy
Wang, W., Liu, J., Feng, W., Du, S., Ge, R., Li, J., Liu, Y., Sun, H., Zhang, D., Zhang, H., et al. (2018) · Biomaterials Science · doi:10.1039/c8bm01414k · Cited by 44
Jang, C. H., Moon, N., Oh, J., & Kim, J. (2019) · Nutrients · doi:10.3390/nu11040770 · Cited by 44
Gain of Function (GOF) Mutant p53 in Cancer—Current Therapeutic Approaches
Roszkowska, K. A., Piecuch, A., Sady, M., Gajewski, Z., & Flis, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113287 · Cited by 48
Homeostasis Imbalance of YY2 and YY1 Promotes Tumor Growth by Manipulating Ferroptosis
Li, Y., Li, J., Li, Z., Wei, M., Zhao, H., Miyagishi, M., Wu, S., & Kasim, V. (2022) · Advanced Science · doi:10.1002/advs.202104836 · Cited by 42
Targeting PARP and autophagy evoked synergistic lethality in hepatocellular carcinoma
Zai, W., Chen, W., Han, Y., Wu, Z., Fan, J., Zhang, X., Luan, J., Tang, S., Jin, X., Fu, X., et al. (2019) · Carcinogenesis · doi:10.1093/carcin/bgz104 · Cited by 46
Zhang, W., Qian, W., Gu, J., Gong, M., Zhang, W., Zhang, S., Zhou, C., Jiang, Z., Jiang, J., Han, L., et al. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215976 · Cited by 43
Xue, Y., Jiang, X., Wang, J., Zong, Y., Yuan, Z., Miao, S., & Mao, X. (2023) · Biomarker Research · doi:10.1186/s40364-022-00433-w · Cited by 43
“Mutation of the TP53 gene is related to many kinds of human cancers [122].”
BackgroundSirtuin1-p53: A potential axis for cancer therapy
Yin, J., Lu, X.-T., Hou, M.-L., Cao, T., & Tian, Z. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115543 · Cited by 44
The crisscross between p53 and metabolism in cancer
Mao, Y., & Jiang, P. (2023) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2023109 · Cited by 45
“In addition to the miraculous effects of ATO in reactivating p53 mutations, a number of approaches have been developed in clinical trials to restore the function of mutant p53 [96].”
BackgroundDefining molecular risk in ALK+ NSCLC
Christopoulos, P., Budczies, J., Kirchner, M., Dietz, S., Sültmann, H., Thomas, M., & Stenzinger, A. (2019) · Oncotarget · doi:10.18632/oncotarget.26886 · Cited by 42
“More frequent radiologic surveillance, additional ctDNA monitoring [20], upfront administration of more potent ALK inhibitors and combination with experimental compounds, such as TP53-directed drugs [70] may also be beneficial, but their clinical utility needs to be tested in prospective Table 2: Characteristics of th…”
BackgroundEmerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer
Lu, Y., Yang, Y., Zhu, G., Zeng, H., Fan, Y., Guo, F., Xu, D., Wang, B., Chen, D., & Ge, G. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.83026 · Cited by 42
“Although degradation of mutant p53 can be induced[68] or function can be restored with arsenic trioxide[69], the existence of different types of p53 mutants can inhibit application of this approach.”
BackgroundMolecular diagnosis of nasopharyngeal carcinoma: Past and future
Hsu, C., Chang, Y., & Li, H. (2024) · Biomedical Journal · doi:10.1016/j.bj.2024.100748 · Cited by 46
“However, some DBD TP53 mutants, such as R175 and R273, can now be partially reactivated or refolded to restore normal function using small molecules including methylene quinuclidinone, CP-31398, PRIMA-1, and ARP-246 [92,95,96].”
He, W., Yan, J., Jiang, W., Li, S., Qu, Y., Niu, F., Yan, Y., Sui, F., Wang, S., Zhou, Y., et al. (2018) · Chemistry of Materials · doi:10.1021/acs.chemmater.8b02572 · Cited by 41
Liu, Y., Huang, W., & Cai, Z. (2020) · Nature Communications · doi:10.1038/s41467-020-19314-7 · Cited by 42
Christopoulos, P., Dietz, S., Kirchner, M., Volckmar, A., Endris, V., Neumann, O., Ogrodnik, S. J., Heußel, C. P., Herth, F. J. F., Eichhorn, M., et al. (2019) · Cancers · doi:10.3390/cancers11010124 · Cited by 39
“One possibility is that other, more basic and still unidentified biologic alterations in TP53 mutated tumours might exert an even more important influence on clinical course, and that these could be active already before TP53 mutations become detectable, which may have implications for the ongoing efforts to target mu…”
BackgroundContribution of Mitochondrial Ion Channels to Chemo-Resistance in Cancer Cells
Peruzzo, R., & Szabó, I. (2019) · Cancers · doi:10.3390/cancers11060761 · Cited by 40
“,[22]) and crucially contribute to drug resistance.”
BackgroundTP53 alterations in relapsed childhood acute lymphoblastic leukemia
Yu, C., Chang, W., Jou, S., Lin, T.-K., Chang, Y., Lin, C., Lin, K., Lu, M., Chen, S., Wu, K., et al. (2019) · Cancer Science · doi:10.1111/cas.14238 · Cited by 40
Metadata
- Authors
- Bykov, V. J. N., Eriksson, S. E., Bianchi, J., & Wiman, K. G.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Wiman, Klas G.
- Venue
- Nature Reviews Cancer
- Published
- 2017-12-15
- Volume
- 18
- Issue
- 2
- Pages
- 89-102
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W2772062014
- Cited by
- 889
- References
- 159
- Citations by year
- 2026: 43 · 2025: 70 · 2024: 100 · 2023: 132 · 2022: 126 · 2021: 150 · 2020: 129 · 2019: 88 · 2018: 49 · 2017: 1
- FWCI
- 7.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- TP53, mutant p53, p53 reactivation, missense mutations, nonsense mutation, tumor suppressor, cancer therapy, cancer cell death, clinical trials
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Mutation, Neoplasms, Tumor Suppressor Protein p53, Cell Death, Mutant Proteins
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